Necroptosis, pyroptosis and apoptosis: an intricate game of cell death

Cell death is a fundamental physiological process in all living organisms.Its roles extend from embryonic development,organ maintenance,and aging to the coordination of immune responses and autoimmunity.In recent years,our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially.Different modalities of what has become known as‘programmed cell death’have been described,and some key players in these processes have been identified.We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death.These studies have highlighted the complex mechanisms tipping the balance between different cell fates.Here,we summarize the latest discoveries in the three most well understood modalities of cell death,namely,apoptosis,necroptosis,and pyroptosis,highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole.

HMGB1, IL-1α, IL-33 and S100 proteins： dual-function alarmins

Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline- encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both intracellular and extracellular functions which have been the subject of intense research. Indeed, alarmins can either exert beneficial cell housekeeping functions, leading to tissue repair, or provoke deleterious uncontrolled inflammation. This group of proteins includes the high-mobility group box 1 protein （HMGB1）, interleukin （IL）-1α, IL-33 and the Ca^2＋-binding S100 proteins. These dual-function proteins share conserved regulatory mechanisms, such as secretory routes, post-translational modifications and enzymatic processing, that govern their extracellular functions in time and space. Release of alarmins from mesenchymal cells is a highly relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases and in cancer development.

How location and cellular signaling combine to activate the NLRP3 inflammasome

NOD-,LRR-,and pyrin domain-containing 3(NLRP3)is a cytosolic innate immune sensor of cellular stress signals,triggered by infection and sterile inflammation.Upon detection of an activating stimulus,NLRP3 transitions from an inactive homo-oligomeric multimer into an active multimeric inflammasome,which promotes the helical oligomeric assembly of the adaptor molecule ASC.ASC oligomers provide a platform for caspase-1 activation,leading to the proteolytic cleavage and activation of proinflammatory cytokines in the IL-1 family and gasdermin D,which can induce a lytic form of cell death.Recent studies investigating both the cellular requirement for NLRP3 activation and the structure of NLRP3 have revealed the complex regulation of NLRP3 and the multiple steps involved in its activation.This review presents a perspective on the biochemical and cellular processes controlling the assembly of the NLRP3 inflammasome with particular emphasis on structural regulation and the role of organelles.We also highlight the latest research on metabolic control of this inflammatory pathway and discuss promising clinical targets for intervention.